This application is a 371 of PCT/JP99/05658 filed Oct. 14, 1999.
The present invention relates to novel aminophenoxyacetic acid derivatives and pharmaceutically acceptable salt thereof, which have neuroprotective effects by inducing or increasing calbindin D28 Kd, one of Ca2+-binding proteins, and which are useful in ameliorating and treating functional and organic disorders in the brain. More specifically, the present invention relates to therapeutic and improving agents for the allevivation or treatment of symptoms due to various ischemic disorders in the brain such as sequelae of cerebral infarction, sequelae of intracerebral hemorrhage, sequelae of cerebral arteriosclerosis and so on, and symptoms of organic brain disorder such as senile dementia, sequelae of head trauma, sequelae of surgical brain operation, Alzheimer""s disease, Parkinson""s disease, amyotrophic lateral sclerosis and so on.
It is generally considered that the pathogenesis of progressive, delayed death of nerve cells, observed in cerebral injury and cerebrovascular disease such as intracerebral hemorrhage, transient ischemia attack, and cerebral infarction, is mainly caused by a rise in intracellular Ca2+ concentration due to various factors related to signal transductions. Such factors related to signal transduction include, for example, abnormal activation of glutamate receptors due to excessive release glutamate, that is, an excitatory neurotransmitter, abnormal activation of ion channels, and excessive production of reactive oxygen species/free radicals. [F. B. Meyer, Brain Res. Rev., 14, 227 (1989); E. Boddeke et al., Trends Phamiacol. Sci., 10, 397 (1989); J. M. McCall et al., Ann. Rep. Med. Chem., 21, 31 (1992)].
From these points of view, medicaments for preventing or suppressing the neuronal cell death, such as glutamate receptor antagonists, calcium channel blockers, antioxidants and so on have been developed. However, these clinically used medicaments suppress only a few pathways related to increase of the cellular Ca2+ concentration, and are not sufficient for preventing or suppressing the neuronal cell death.
On the contrary, calbindin D28 Kd, one of Ca2+-binding proteins and mainly distributed in friable site of the brain against ischemic disease, is reported to possess buffering effects for a rise in cytotoxic intracellular Ca2+ concentration. [A. M. Lacopino et al., Neurodegeneration, 3, 1 (1994); M. P. Mattson et al., Neuron, 6, 41 (1991)].
Accordingly, it is expected to achieve sufficient neuroprotective effects against the increase of intracellular Ca2+ concentration caused by any kinds of pathways if calbindin D28 Kd, one of the Ca2+-binding proteins per se, can be supplied in a living body. That is, it is expected that medicaments containing calbindin D28 Kd would be effective therapeutic and improving agents for the allevivation or treatment of symptoms due to various ischemic disorders in the brain such as sequelae of cerebral infarction, sequelae of intracerebral hemorrhage, sequelae of cerebral arteriosclerosis and so on, and symptoms of organic brain disorder such as senile dementia, sequelae of head trauma, sequelae of surgical brain operation, Alzheimer""s disease, Parkinson""s disease, amyotrophic lateral sclerosis and so on.
However, because calbindin D28 Kd is unstable macromolecular protein having 28 Kd (kilo dalton) of molecular weight, it is difficult to be administered directly into a site in the central nervous system of a living body in view of pharmacological and pharmaceutical standpoints.
On the other hand, the lower molecular compounds having effect on induction of the calbindin D28 Kd can be easily prepared into the various kinds of pharmaceutical compositions by the conventional techniques. Thus, these lower molecular compounds are expected to induce the calbindin D28 Kd after administration in to a body, and to possess buffering action against the increase of the cellular Ca2+ concentration. That is, these lower compounds can be effective compounds for improving and treating cerebral functional and organic disorders.
Under these circumstances, the objective of the present invention is to provide the lower molecular weight compounds having neuroprotective effect by inducing the calbindin D28 Kd, one of Ca2+-binding proteins, of low toxicity in suitable preparations of pharmaceutical compositions such as intravenous injectable solution.
The further purpose of the present invention is to provide the therapeutic and improving agents for the allevivation or treatment of symptoms due to various ischemic disorders in the brain such as sequelae of cerebral infarction, sequelae of intracerebral hemorrhage, sequelae of cerebral arteriosclerosis and so on, and symptoms of organic brain disorder such as senile dementia, sequelae of head trauma, sequelae of surgical brain operation, Alzheimer""s disease, Parkinson""s disease, amyotrophic lateral sclerosis and so on.
As one aspect of the present invention, it is provided aminophenoxyacetic acid derivatives represented by the following formula (I): 
wherein:
R1, R2, R3 and R4 are, independent from each other, hydrogen atom; halogen atom; hydroxy group; alkoxy group which may be substituted; alkyl group which may be substituted; aryl group which may be substituted; or aralkyl group which may be substituted;
R5, R6, R7 and R8 are, independent from each other, hydrogen atom; alkyl group which may be substituted; aryl group which may be substituted; or aralkyl group which may be substituted;
E1 is oxygen atom; sulfur atom; or group xe2x80x94NR9xe2x80x94 (in which, R9 is hydrogen atom; alkyl group which may be substituted; aryl group which may be substituted; or aralkyl group which may be substituted);
E2 is oxygen atom; sulfur atom; or group xe2x80x94NR10xe2x80x94 (in which, R10 is hydrogen atom; alkyl group which may be substituted; aryl group which may be substituted; or aralkyl group which may be substituted);
n is 0 to 5;
X and Y are, independent from each other, connecting bond; alkylene group which may be substituted by hydroxyl group, carboxyl group, oxo group or morpholinyl group; cycloalkylene group; alkenylene group which may be substituted by lower alkyl group; xe2x80x94NHCOxe2x80x94; xe2x80x94CONHxe2x80x94; or xe2x80x94SO2xe2x80x94; or xe2x80x94Xxe2x80x94Yxe2x80x94 represents xe2x80x94CON(CH3)xe2x80x94;
Q is hydrogen atom; naphthyl group; phenyl group which may be substituted; phenoxy group which may be substituted; benzoyl group which may be substituted; pyridyl group which may be substituted; quinolyl group which may be substituted; isoquinolyl group which may be substituted; or benzimidazolyl group which may be substituted; (provided that one of E1 and E2 represent either oxygen atom or sulphur atom then the other one of E1 and E2 represent neither oxygen atom nor sulfur atom at the same time, and in the case of E1 is nitrogen atom and E2 is oxygen atom, or in the case of E1 is oxygen atom and E2 is nitrogen atom, all of the groups of R1, R2, R3 and R4 do not represent methyl group at the same time), or pharmaceutically acceptable salts thereof.
More specifically, the present invention provides the aminophenoxyacetic acid derivatives of the formula (I), in which;
1. R1, R2, R3 and R4 are, independent from each other, hydrogen atom; halogen atom; alkoxy group; or alxyl group which may be substituted; R5 is hydrogen atom or alkyl group which may be substituted; E1 is xe2x80x94NHxe2x80x94; and E2 is oxygen atom,
2. E1 is xe2x80x94NHxe2x80x94; E2 is oxygen atom; either the case in which X is connecting bond and Y is group xe2x80x94CONHxe2x80x94, or the other in which X is the group xe2x80x94CONHxe2x80x94 and Y is connecting bond; Q is phenyl group which may be substituted, and
3. E1 and E2 are xe2x80x94NHxe2x80x94; X and Y are connecting bond; Q is phenyl group which may be substituted,
or pharmaceutically acceptable salts thereof.
According to the present inventor""s investigations, it is confirmed that the aminophenoxyacetic acid in low concentration represented by the formula (I) effectively induced the calbindin D28 Kd and possessed excellent neuroprotective effect accordingly. Further, these compounds are also confirmed to have high safety margin, and are suitable for preparation of various kinds of pharmaceutical compositions.
Therefore, the. present invention provides the calbindin D28 Kd, inducing agent containing aminophenoxyacetic acid derivatives represented by the formula (I) or pharmaceutically acceptable salts thereof as an active ingredient, as another embodiment.
As still a further embodiment, the present invention provides an improving and therapeutic agent for the cerebral functional and organic disorders containing aminophenoxyacetic acid derivatives represented by the formula (I) or pharmaceutically acceptable salt thereof, as an active ingredient.
Although lower molecular weight compounds, the aminophenoxyacetic acid derivatives of the formula (I) express the neuroprotective effect by inducing the calbindin D28 Kd after administration into a living body.
Accordingly, as still another embodiment, the present invention provides a method for selecting a neuroprotective compound by measurement of inducing capability of calbindin D28 Kd, which is Ca2+-binding protein.
As still another embodiment. the present invention provides neuroprotective compounds to induce the calbindin D28 Kd, one of Ca2+-binding proteins.
As still a further embodiment, the present invention provides therapeutic and improving agents containing compounds having neuroprotective effect by inducing the calbindin D28 Kd, against cerebral function disorders due to various ischemic disorders such as cerebral infarction, intracerebral hemorrhage and cerebral arteriosclerosis.
As still a further embodiment, the present invention provides therapeutic and improving agents containing compounds having neuroprotective effect by inducing calbindin D28 Kd, for cerebral organic disorders such as senile dementia, cerebral injury, sequela of cerebral surgical operation, Alzheimer""s disease, Parkinson""s disease, and amyotrophic lateral sclerosis.
As a preferred embodiment, the present invention provides the aminophenoxyacetic acid derivatives represented by the formula (I) or pharmaceutically acceptable salt thereof is the pharmaceutical composition containing the compounds having neuroprotective effect by inducing the calbindin D28 Kd.
The aminophenoxyacetic acid derivatives of the present invention include aminophenoxyacetic acids, aminoanilinoacetic acids, aminothiophenoxyacetic acids, oxyanilinoacetic acids and thioanilinoacetic acids. Therefore, xe2x80x9caminophenoxyacetic acid derivativesxe2x80x9d in this specification include all the derivatives stated above as long as not stated otherwise.
In the aminophenoxyacetic acid derivatives of the formula (I) provided by the present invention with reference to various substitution group of R1 to R10, xe2x80x9chalogen atomxe2x80x9d includes fluorine atom, chlorine atom and bromine atom.
The term xe2x80x9calkoxy groupxe2x80x9d stands for a straight-chained or branched-chained C1-C5 alkoxy group, and may include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy and the like.
The term xe2x80x9calkyl group which may be substitutedxe2x80x9d stands for a straight-chained or branched-chained C1-C5 alkyl group which may be halogen-substituted, and may include, for example, methyl, ethyl, propyl, trifluoromethyl group, and the like.
The xe2x80x9carylxe2x80x9d, a part of the, term xe2x80x9caryl group which may be substitutedxe2x80x9d, stands for C4-C14 aryl group or heteroaryl group which may contain one or more of hetero ring atom(s) such as nitrogen and oxygen atom(s). Examples of the preferred xe2x80x9carylxe2x80x9d include phenyl, pyridyl and naphthyl. The suitable substituents of said aryl group include halogen atom such as fluorine atom, chlorine atom and bromine atom; hydroxy group; a straight-chained or branched-chained C1-C5 alkoxy group such as methoxy and ethoxy group; and a straight-chained or branched-chained C1-C5 alkyl group which can be substituted by halogen atom such as methyl, ethyl, propyl and trifluoromethyl.
The xe2x80x9caralylxe2x80x9d, a part of the term xe2x80x9caralkyl group which may be substitutedxe2x80x9d, stands for C5-C12 aralkyl group or heteroarylalkyl group, which may contain one or more of hetero ring atom such as nitrogen and oxygen atom(s). The examples include benzyl, phenethyl, pyridylmethyl, and pyridylethyl. The suitable substituents of said aralkyl group include halogen atoms such as fluorine atom, chlorine atom and bromine atom; hydroxy group; a straight-chained or branched-chained C1-C5 alkoxy group such as ethoxy group; and a straight-chained or branched-chained C1-C5 alkyl group which may be substituted by halogen atom such as methyl, ethyl, propyl and trifluoromethyl.
The xe2x80x9calkylenexe2x80x9d, a part of the term xe2x80x9calkylene group which may be substituted by hydroxyl groupxe2x80x9d, refers to the substituents X and Y, and preferably represents a straight-chained or branched-chained C1-C6 alkylene group such as methylene, methylmethylene, ethylene, trimethylene, tetramethylene, cyclopropylmethylene and the like.
The term xe2x80x9ccycloalkylenexe2x80x9d preferably stands for C3-C6 cycloalkylene and may include 1,1-cyclopropylene, 1,2-cyclopropylene, 1,1-cyclobutylene, 1,1-cyclopentylene, 1,1-cyclohexylene and the like. Among them, 1,1-cyclopropylene and 1,2-cyclopropylene are more preferable.
The xe2x80x9calkenylenexe2x80x9d, a part of the term xe2x80x9calkenylene group which may be substituted by lower alkyl groupxe2x80x9d, may include C2-C4 alkenylene such as vinylene, and butadiene and vinylene is preferably used. The lower alkyl group, which is substituent of alkylene group, may be methyl, ethyl, propyl, isopropyl and the like.
The suitable substituents represented as xe2x80x9cQxe2x80x9d for xe2x80x9cphenyl group which may be substitutedxe2x80x9d, xe2x80x9cphenoxy group which may be substitutedxe2x80x9d, xe2x80x9cbenzoyl group which may be substitutedxe2x80x9d, xe2x80x9cpyridyl group which may be substitutedxe2x80x9d, xe2x80x9cquinolyl group which may be substitutedxe2x80x9d, xe2x80x9cisoquinolyl group which may be substitutedxe2x80x9d and xe2x80x9cenzimidazolyl group which may be substitutedxe2x80x9d, may include a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom; a hydroxyl group; a straight-chained or branched-chained C1-C5 alkoxy group such as methoxy, ethoxy group and so on. Furthermore, these substituents may also include a straight-chained or branched-chained C1-C5 alkyl group which may be substituted by halogen atom such as fluorine atom, chlorine atom and bromine atom. The examples include methyl, ethyl, propyl, trifluoromethyl and the like. Still further, these substituents include a carboxyl group, a carbamoyl group and an amino group.
The term xe2x80x9cconnecting bondxe2x80x9d with reference to xe2x80x9cXxe2x80x9d and xe2x80x9cYxe2x80x9d means direct bond. Therefore, if xe2x80x9cXxe2x80x9d and/or xe2x80x9cYxe2x80x9d are connecting bond, two adjacent substituents of xe2x80x9cXxe2x80x9d and/or xe2x80x9cYxe2x80x9d are connected directly, and these substituents do not exist as xe2x80x9cXxe2x80x9d and/or xe2x80x9cYxe2x80x9d.
It is understood that when the aminophenoxyacetic acid derivatives of the formula (I) of the present invention exist in the isomer forms, each isomers per se, as well as the isomeric mixture, shall be included in the compounds of the present invention. Namely, the structural isomers may exist due to the substituents on the benzene ring. Furthermore, optical isomers may exist due to the asymmetric carbon atom of the hydroxy substituted xe2x80x9cXxe2x80x9d or xe2x80x9cYxe2x80x9d of alkylene group. These isomers shall be included within the scope of the compounds of the present invention.
The aminophenoxyacetic acid derivatives of the formula (I) include the compounds (Ia), (Ib) and (Ic) obtained by the synthetic process mentioned latter. For example, these compounds may be prepared by the following.
The compound (IV), obtained by the reaction of the compound (II) with the ester compound (III), is hydrolyzed to convert into carboxylic acid derivative (V). The obtained compound (V) is then converted into amide compound (VII) by the condensation reaction with the compound (VI). Further, the protecting group in the compound (VII) thus obtained is removed to obtain compound (Ia), the compound of formula (I) of the present invention, in which n is 0, X and Y are each a connecting bond and Q is a hydrogen atom (Process 1).
The compound (Ib) can be obtained by reacting the compound (Ia) with the compound (VIII) (Process 2).
Furthermore, the compound (Ic) can be obtained by reacting the compound (Ia) with the compound (IX) (Process 3).
Each process will be further illustrated by the following eaction scheme. 
wherein R1 to R8, E1 and E2 have the same definitions as above, and R11 is alkl group which may be substituted, aryl group which may be substituted; aralkyl group which may be substituted; tert-butoxycarbonyl group; ethoxycarbonyl group; acetyl group; benzyloxycarbonyl group; p-methoxybenzyloxycarbonyl group; R12 is a straight-chained or branched-chained C1-C5 alkyl group; L1 is leaving group which can easily be replaced with amino, hydroxy and mercapto group; P is benzyl group, tert-butoxycarbonyl group, ethoxycarbonyl group; acetyl group; benzyloxycarbonyl group; p-methoxybenzyloxycarbonyl group.
According to this process 1, the compound (Ia) can be obtained from the known starting compound (II).
Namely, for the first step, the compound (II) is reacted with 1.0 to 1.5 mole equivalent of ester compound (III) in the inert solvent, and if necessary in the presence of the base, under stirring at xe2x88x9220xc2x0 C. to 150xc2x0 C., preferably at 0xc2x0 C. to 100xc2x0 C.
The inert solvent to be used in the reaction may be benzene, toluene, tetrahydrofuran, dioxane, dimethyform ride, dimethyl sulfoxide, acetonitrile, acetone, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, ethylene glycol and the like.
The base to be used in the above reaction may be an organic base such as triethylamine, diisopropylethylamine, pyridine and the like, or an inorganic base such as sodium, sodium hydride, potassium, potassium hydride, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, sodium bicarbonate, potassium bicarbonate and the like. These organic base and inorganic base may be used in combination, and sodium iodide or tetrabutylammonium iodide can be added in the reaction mixture.
The substituent xe2x80x9cL1xe2x80x9d in the ester compound (III) may be the leaving group which can easily be replaced with amino, hydroxy and mercapto group, and examples include halogen atom such as chlorine atom, bromine atom, iodide atom; allylsulfonyloxy group such as methanesulfonyloxy group; arylsulfonyloxy group such as p-toluenesulfonyloxy group, 3-nitrobenzenesulfonyloxy group and the like.
The compounds (II) and (III) to be used in this reaction are commercial available ones, or can easily prepared by the known methods.
The compound (II) and compound (III) to be used in this reaction can be commercially available and known compounds, or can be easily prepared from known compounds by using common methods.
Examples of the compound (II) include 4-(tert-butoxycarbonylamino)phenol, 4-(tert-butoxycarbonylamino)-2,3,5-trimethylphenol, 4-(tert-butoxycarbonylamino)-2-chloro-3,5,6-trimethylphenyl, 4-(tert-butoxycarbonylamino)-2,3,6-trimethylphenol, 4-(tert-butoxycarbonylamino)-2,3-dimethylphenol, 4-(tert-butoxycarbonylamino)-2,5-dimethylphenol, 2-(tert-butoxycarbonylamino)-4,6-dimethylphenol, 5-(tert-butoxycarbonylamino)-2-methoxyphenol, 5-(tert-butoxycarbonylamino)-4-chloro-2-methoxyphenol, 4-(tert-butoxycarbonylamino)-2,6-dichlorophenol, 4-(tert-butoxycarbonylamino)-2,3,5,6-tetramethylaniline, 4-methoxy-2-methylaniline, 4-(tert-butoxycarbonylamino)-2,5,-dimethylaniline, 2-(tert-butoxycarbonylamino)-4,5-dimethylaniline, 3-(tert-butoxycarbonylamino)-2,4,6-trimethylaniline, 4-(tert-butoxycarbonylamino)-2,5-dichloroaniline, 4-(tert-butoxycarbonylamino)-2,6-dichloroaniline, 2-(tert-butoxycarbonylamino)-3,4-dichloroaniline, 4-(tert-butoxycarbonylamino)-2-methoxy-5-methylaniline, 4-(tert-butoxycarbonylamino)-2,5-dimethoxyaniline, 4-(benzyloxycarbonylamino)phenol, 4-(benzyloxycarbonylamino)-2,3,5-trimethylphenol, 4-(benzyloxycarbonylamino)-2-chloro-3,5,6-trimethylphenol, 4-(benzyloxycarbonylamino)-2,3,6-trimethylphenol, 4-(benzyloxycarbonylamino)-2,3-dimethylphenol, 4-(benzyloxycarbonylamino)-2,5-dimethylphenol, 2-(benzyloxycarbonylamino)-4,6-dimethylphenol, 5-(benzyloxycarbonylamino)-2-methoxyphenol, 5-(benzyloxycarbonylamino)-4-chloro-2-methoxyphenol, 4-(benzyloxycarbonylamino)-2,6-dichlorophenol, 4-(benzyloxycarbonylamino)-2,3,4,6-tetramethylaniline, 4-(benzyloxycarbonylamino)-2,5-dimethylaniline, 2-(benzyloxycarbonylamino)-4,5-dimethylaniline, 3-(benzyloxycarbonylamino)-2,4,6-trimethylaniline, 4-(benzyloxycarbonylamino)-2,5-dichloroaniline, 4-(benzyloxycarbonylamino)-2,6-dichloroaniline, 2-(benzyloxycarbonylamino)-3,4-dichloroaniline, 4-(benzyloxycarbonylamino)-2-methoxy-5-methylaniline, 4-(benzyloxycarbonylamino)-2,5-dimethoxyaniline and so on.
The ester compound of the formula (III) includes, for example, ethyl bromoacetate, ethyl 2-bromopropionate, ethyl 2-bromo-2-methylpropionate, and so on.
Then, the obtained compound (IV) is hydrolyzed to convert into carboxylic acid derivative (V) by the common methods, and the resultant carboxylic acid derivative of the formula (V) is further converted into amide derivative (VII) by reaction with the compound (VI).
The compound (VI) to be used for the reaction with the compound (V) is known compound as described in J. Med. Chem., 36, 3707 (1993) [R. H. Mach et al.], or can be easily prepared by the methods described in EP 0184257 A1 [R. A. Stokbroekx, et al.].
The reaction conditions of this amidation reaction may vary according to the methods described in xe2x80x9cCompendium for Organic Synthesisxe2x80x9d (wiley-Interscience: A Division of John Wiley and Sons Ltd.). For example, the compound (V) is treated optionally in the presence of an organic or an inorganic base with diethyl cyanophosphonate (DEPC), diphenylphosphoryl azide (DPPA), dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2-iodo-1-methylpyridinium iodide or benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP Reagent), and then reacted with compound (VI) to obtain the amide compound (VII). Furthermore, the compound (V) is converted into the activated ester compound such as acid halide, symmetric acid anhydride, or the mixture acid anhydride, then reacted with the compound (VI) to obtain the amide compound (VII).
The compound (VII) thus obtained is converted into the aminophenoxyacetic acid derivatives of the formula (Ia), the compound of the present invention, by the removal reaction of the protecting group on the nitrogen atom of the amide compound (VII).
This reaction may vary depend on the protecting group on the nitrogen atom of the compound (VII). For example, the compound (VII) is treated with acids such as trifluoroacetic acid, hydrogen chloride, hydrogen bromide, or sulfuric acid in an inert solvent such as benzene, toluene, acetonitrile, tetrahydrofuran, dioxane, chloroform, carbon tetrachloride, and the like. Furthermore, the removal of the protecting group may also be carried out by hydrogenolysis of the compound (VII) under 1 to 5 atm of hydrogen, in the presence of a catalyst such as palladium-carbon, palladium hydroxide, platinum, or platinum oxide, in an inert solvent such as methanol, ethanol, isopropyl alcohol, ethyl acetate or acetic acid.
Although each compounds obtained in the above process 1 may be used for the next reaction without further purification, it can also be used after further purification in conventional manner such as recrystallization or column chromatography and so on if necessary. 
wherein R1 to R8, E1, E2, n, X and Y have the same definitions as above; and Qxe2x80x2 is phenyl group which may be substituted, phenoxy group which may be substituted, benzoyl group which may be substituted, pyridyl group which may be substituted, quinolyl group which may be substituted, isoqunolyl group which may be substituted, or benzimidazolyl group which may be substituted; L2 is leaving group which can be easily replaced with the amino group.
According to this process 2, the aminophenoxyacetic acid of the formula (Ib) of the present invention can be obtained by reacting the compound (Ia), obtained in the process 1 mentioned above, with the compound (VIII).
The compound (Ia) is reacted with 1.0 to 1.5 mole equivalent of the compound (VIII) in the inert solvent such as benzene, toluene, acetonitrile, ether, tetrahydrofuran, dioxan, methylene chloride, chloroform, carbon tetrachloride, dimethylformamide, and dimethyl sulfoxide in the presence of the base, at xe2x88x9250xc2x0 C. to 120xc2x0 C., preferably at xe2x88x9220xc2x0 C. to 50xc2x0 C.
The base to be used in the reaction may be an organic base such as triethylamine, pyridine, diisopropylethylamine and the like, or an inorganic base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, cesium fluoride, sodium hydride and the like. Sodium iodide or tetrabutylamonium iodide can be added in the reaction mixture.
The substituent xe2x80x9cL2xe2x80x9d in the compound (VIII) is the leaving group, which can easily be replaced by amino group, and examples include halogen atom such as chlorine atom, bromine atom; alkylsulfonyloxy group such as methanesulfonyloxy group; arylsulfonyloxy group such as p-toluenesulfonyloxy group and the like.
In this process 2, the aminophenoxyacetic acid of the formula (Ib) can be produced as well. 
wherein R1 to R8, E1, E2, Q and L2 have the same definitions as previously mentioned, and p is 0 to 3.
According to this process 3, the aminophenoxyacetic acid of the formula (Ic) of the present invention can be obtained from the reaction of the compound (Ia), obtained in the process 1 mentioned above, with the compound (IXa) or the compound (IXb).
For example, the compound (Ia) is reacted with 0.9 to 1.5 mole equivalent of the compound (IXa) or (IXb) in an inert solvent at from room temperature to about 200xc2x0 C., preferably at about 50xc2x0 C. to about 150xc2x0 C., to produce the aminophenoxyacetic acid of the formula (Ic).
The inert solvent to be used in the reaction may be benzene, toluene, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, dioxane, dimethyformamide, dimethyl sulfoxide, acetonitrile, methanol, ethanol, isopropyl alcohol, t-butyl alcohol, ethylene glycol and the like.
Examples of the compound (IXa) include epibromohydrin, epichlorohydrin, (R)-epichlorohydrin, (S)-epichlorohydrin and the like, and examples of the compound (IXb) include glycidyl tosylate, (R)-glycidyl tosylate, (S)-glycidyl tosylate, (R)-glycidyl 3-nitrobenzensulfonate, (S)-glycidyl 3-nitrobenzensulfonate, (R)-glycidyl 4-nitrobenzoate, (S)-glycidyl 4-nitrobenzoate, gylcidyltrimethylammonium chloride and the like.
In this process 3, the aminophenoxyacetic acid of the formula (Ic) can be produced as well.
The aminophenoxyacetic acid derivatives of the formula (I) thus obtained may be isolated and purified in conventional manner, such as recrystallization, column chromatography and the like.
Further, each isomers contained in the compounds of the formula (I) of the present invention can be obtained by resolution of the isomeric mixture of these compounds by the conventional methods, such as recrystallization, column chromatography, HPLC, and the like, or by using optically active reagents.
The compounds of the present invention represented by the formula (I) may be used in the form of free bases or suitable pharmaceutically acceptable acid addition salts thereof. The pharmaceutically acceptable salts can be obtained by treating the compound (I) with an inorganic acid or an organic acid in suitable solvent. Examples of the inorganic acid include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, periodic acid and the like. Further, examples of the organic acid include formic acid, acetic acid, butyric acid, oxalic acid, malonic acid, propionic acid, valeric acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid and the like.
The aminophenoxyacetic acid of the present invention represented by the formula (I) or pharmaceutically acceptable salts thereof shows low toxicity and may be administered per se. However, it may be converted in the form of pharmaceutically acceptable composition with the conventionally pharmaceutically acceptable carriers for improvement or treatment of ischemic diseases.
The dosage forms may include oral formulations such as capsules, tablets or parenteral formulations such as injection solution containing the compound of the formula (I) per se, or using the conventional excipients. For example, the capsules can be prepared by mixing the compound of the formula (I) in powder form with a suitable excipient such as lactose, starch or derivatives thereof or cellulose derivatives, and then filled in gelatin capsules.
Also, the tablets can be prepared by mixing the active ingredients with the above-mentioned excipients, binders such as sodium carboxymethylcellulose, alginic acid or gum arabic and water, then if necessary, making the resultant mixture into granules. Then, it may be further mixed with lubricant such as talc or stearic acid, and compressed into tablet by mean of common tableting machine.
Injectable formulations for parenteral route also can be prepared by dissolving the compound of the formula (I) or salts thereof in sterile distilled solution or sterile physiological saline solution with solution adjuvant, and filling it into ample. A stabilizer or buffer can be used in the injectable solution, and the injectable formulation may be administered intravenously or by dripping.
In administration of the compound of the formula (I) which possess neurocytic protecting effect based on induction of calbindin D28 Kd, one of Ca2+-bindind proteins, the therapeutically effective dosage for improving cerebral functional and organic disorders is not particularly limited and may vary depending on the various kinds of factors. These factors may be the patient""s condition, the severity of the disease, age, existence of a complication, administration route, formulation, as well as number of times for administration.
A usual recommended daily dose for oral administration is within the range of 0.1-1,000 mg/day/person, preferably 1-500 mg/day/person, while a usual recommended daily dose for parenteral administration is within the range of {fraction (1/100)} to xc2xd based on dose of the oral administration. These doses also may vary depending on age, as well as the patient""s condition.